Neogenin, a Dependence and Guidance Receptor

A pair of papers explores the functions of repulsive guidance molecule (RGM) and finds that its receptor, neogenin, mediates both guidance signals and cell survival signals. Rajagopalan et al. report the identification of neogenin as the high-affinity receptor for RGM by expression cloning. The role of neogenin in axon repulsion was confirmed in two different assays using either function-blocking antibodies against neogenin or a soluble recombinant C-terminal fragment of neogenin. Introduction of neogenin into dorsal root ganglion cells caused those cells to avoid RGM. In the second article, Matsunaga et al. electroporated RGM and neogenin, alone or in combination, into chicken embryo brains to study the effects of overexpression. Surprisingly, neogenin alone caused the loss of neurons and an increase in TUNEL-positive cells, indicative of apoptosis. Overexpression of RGM or RGM and neogenin did not produce an increase in cell death. Although netrin can bind neogenin, netrin did not rescue cells from death when neogenin was overexpressed. Repression of RGM with short interfering RNAs also caused caspase-3 activation and cell death. Similar results were obtained in cultured cells. These results are consistent with neogenin's being a dependence receptor. Similar to other dependence receptors, neogenin itself is cleaved by caspases (in vitro assay with caspase-3 and the intracellular domain of neogenin). When in ovo or in cultured cells, neogenin with a mutation in the caspase cleavage site failed to stimulate cell death. Furthermore, the N-terminal portion of neogenin that remains after truncation at the caspase cleavage site is proapoptotic in cultured cells and in vivo. RGM failed to rescue cells from death caused by the N-terminal portion of neogenin, which suggests that RGM prevents caspase cleavage of the receptor.